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ABSTRACT The cytokines interleukin (IL)-4 and IL-13, signaling via the IL-4 receptor (IL-4R), orchestrate type 2 immunity to helminth infections and toxins. Activation of epithelial and

myeloid cells, and a transient neutrophils influx initiates type 2 immune responses, which are dominated by basophils, eosinophils, mast cells, B cell immunoglobulin E production, and type 2

 T helper and T follicular helper cells. Interestingly, IL-4 and IL-13 can curtail chemotaxis and several effector functions of neutrophils in mice and humans. This inhibitory role of IL-4

and IL-13 probably developed to limit tissue damage by neutrophils during type 2 immunity where a “weep and sweep” response aims at expulsion and decreased fecundity, instead of killing, of

macroparasites. Here, we review when IL-4R signaling cytokines appeared during evolution relative to neutrophils and adaptive immunity. Neutrophil-like granular phagocytes were present in

invertebrates throughout the bilaterian clade, but we were unable to find data on IL-4, IL-13, or their receptors in invertebrates. Conversely, vertebrates had both adaptive immunity and

IL-4, IL-13, and IL-4Rs, suggesting that type 2 cytokines evolved together with adaptive immunity. Further studies are necessary to determine whether IL-4R signaling in neutrophils was

established simultaneously with the appearance of adaptive immunity or later. SIMILAR CONTENT BEING VIEWED BY OTHERS BASOPHILS PRIME GROUP 2 INNATE LYMPHOID CELLS FOR NEUROPEPTIDE-MEDIATED

INHIBITION Article 17 August 2020 ELUCIDATING DIFFERENT PATTERN OF IMMUNOREGULATION IN BALB/C AND C57BL/6 MICE AND THEIR F1 PROGENY Article Open access 15 January 2021 COOPERATION OF ILC2S

AND TH2 CELLS IN THE EXPULSION OF INTESTINAL HELMINTH PARASITES Article 05 October 2023 INTRODUCTION Interleukin (IL)-4 and IL-13 are well known for their key roles in type 2 immune

responses, which result in resistance to helminth parasites and inactivation of toxins. IL-4 and IL-13 induce differentiation of naïve T cells to type 2 T helper and T follicular helper

cells, B cell antibody production and isotype switching to immunoglobulin E (IgE), expansion of basophils and eosinophils, mast cell activation, skewing of macrophages toward the subtype of

alternatively-activated macrophages (also known as type 2 or M2 macrophages), and goblet cell hyperplasia [1, 2]. It is well established that neutrophils are present in type 1 and type 3

immune responses, which serve to fight intracellular and extracellular pathogens, respectively. However, recent evidence has revealed a role for neutrophils in protection against parasite

infections [3, 4]. Thus, it was shown that during the initial phase of type 2 responses, the presence of neutrophils was beneficial for limiting parasite survival and spreading. This was

primarily due to formation of neutrophil extracellular traps (NETs) and degranulation [5]. Accordingly, also in type 2 immune responses, neutrophils seem to be the first nonresident immune

cells to arrive to the affected site. Despite their very short lifespan, neutrophils are able to shape the immune response long after their death, for example by guiding and attracting other

immune cells or by their ability to prime macrophages to become M2 macrophages [6]. These M2 macrophages are efficient in protecting during a secondary infection. Thus, neutrophils do not

only leave a temporary mark but are able to impact future immune responses. However, there is accumulating evidence showing that IL-4- and IL-13-mediated IL-4 receptor (IL-4R) signaling in

both mouse and human neutrophils inhibits their migration and effector functions in vitro and in vivo [7, 8]. In a number of different mouse models including sterile inflammation, bacterial

infection, helminth infestation, and rheumatoid arthritis, IL-4R signaling was shown to have an inhibitory effect on neutrophils [9,10,11,12]. Human neutrophils isolated from allergic

patients, a condition dominated by the presence of IL-4 and IL-13, were less capable of migrating and producing NETs than neutrophils from healthy donors [13]. Thus, we hypothesize that

inhibition of neutrophil effector functions in type 2 immune responses constitutes a crucial effect of the IL-4/IL-13–IL-4R system. Failure of this regulatory system can cause detrimental

tissue damage, as seen with neutrophilic types of asthma. Why neutrophils are beneficial for type 2 immune responses and, simultaneously, type 2 cytokines restrict neutrophil effector

functions, can be explained when considering the timing of events. During the initiation phase of a type 2 immune response, there is little or no type 2 cytokines present, and neutrophils

are needed as a first wave of defense. Once the type 2 immune response is fully active, abundant IL-4 and IL-13 suppress neutrophil effector functions, which at this stage—via neutrophil

degranulation and NET formation—would cause excessive tissue damage. Thus, timed IL-4R signaling in neutrophils allows early influx but limits tissue damage by neutrophils during the “weep

and sweep” phase of type 2 immunity. Considering this IL-4R-mediated mechanism of neutrophil regulation, we wondered whether IL-4R signaling cytokines initially evolved to refine adaptive

immune responses against parasites or to provide timed inhibition of innate immune cells, such as neutrophils, to limit tissue damage. In order to address this question, we reviewed and

combined phylogenetic data on neutrophils, the adaptive immune system, and the IL-4/IL-13–IL-4R system. THE EVOLUTION OF NEUTROPHILS Neutrophils are the most abundant leukocytes in human

blood and are typically the first nonresident immune cells to respond to an inflammatory or infectious stimulus [14]. Thus, together with barrier epithelial cells and resident immune cells,

neutrophils form the first line of defense to limit pathogens until the adaptive immune response arrives [15]. Neutrophils are able to fight infection by phagocytosis, release of

antimicrobial effector molecules (termed degranulation), production of reactive oxygen species (ROS), and the formation of NETs, which are DNA meshes decorated with antimicrobial peptides

that neutrophils can expulse in response to pathogens that are too large to phagocytose [8, 16,17,18,19]. Phagocytosis, one of the key effector functions of mammalian neutrophils, is a

ubiquitously present process throughout nature from unicellular amoebae to multicellular organisms [20]. In basic invertebrates, such as sponges or cnidarians, specialized phagocytic cells

called amoebocytes are responsible for taking up foreign material and debris, but in some cases also food particles [21,22,23]. Protostomes and invertebrate deuterostomes all have more or

less complex innate immune systems consisting of non-granular and granular hemocytes. Hemocytes are mesoderm-derived cells that recognize and phagocytose nonself particles and release

antimicrobial granules, thus being reminiscent of monocytes, macrophages, and granulocytes of higher vertebrates [23, 24]. The demonstration of DNA extracellular trap formation not only in

mammalian neutrophils and eosinophils [25], but also in granulocytes of fish [26], crustaceans [27], molluscs [28, 29], and worms [30], provides further evidence of functional analogies

between mammalian and invertebrate granulocytes. Also the production of ROS by oxidase enzyme complexes has been shown in numerous invertebrate species [31]. Moreover, histological stainings

of invertebrate granular hemocytes show acidophilic (i.e., eosinophilic), basophilic, and neutrophilic cells with multi-lobulated nuclei [23]. All these striking morphological and

functional parallels lead to the conclusion that granular phagocytes (i.e., neutrophils) are a well-conserved and phylogenetically ancient immune cell type (Fig. 1). THE EVOLUTION OF

ADAPTIVE IMMUNITY The adaptive immune system of jawed vertebrates (gnathostomes) centers around the genes responsible for recombination of antigen receptors. The evolution of this branch of

immunity is closely linked to two major evolutionary events: the emergence of recombinase-activating gene 1 and 2 (RAG1 and RAG2) and the occurrence of several rounds of whole genome

duplication (WGD). In gnathostomes, RAG proteins are expressed in developmental stages of B and T cells, and are responsible for the random joining of one variable, one joining, and—in some

cases—one diversity gene segment of the antigen receptor gene locus. This process, also termed V(D)J recombination, allows the creation of a vast variety of different receptors from a

relatively low number of single gene segments [32]. _Rag_ or _Rag_-like genes can be found throughout the superphylum of deuterostomes, and a gene related to _Rag1_ called _Transib_ was also

found in insects (e.g., _Helicoverpa zea_). Surprisingly, Transib and RAG1 proteins have very similar enzymatic activity and specificity and the catalytic triad is conserved in both [33].

This suggests that the ancestor of modern-day _Rag_ was acquired by a common ancestor of protostomes and deuterostomes. While _Rag_-like genes are ancient and well conserved, their function

changed during evolution: _Transib_ and active _Rag_-like loci in invertebrates act as transposons, i.e., DNA segments coding for a protein that excises their own DNA segment and inserts it

at another site in the genome. RAG proteins in jawed vertebrates, however, act as recombinases; they do not excise their own gene but DNA in between variable, diversity, and joining gene

segments [34]. Interestingly, cyclostomes, the only living jawless vertebrates, do not have _Rag_ but they have an adaptive immune system based on recombination of leucine-rich repeats

leading to the generation of specific agglutinins called variable lymphocyte receptors that are membrane-bound or secreted [32]. Collectively, the presence of _Rag_-related genes is

widespread throughout the bilaterian clade, but only gnathostomes use RAG as a recombinase which enables the development of a _bona fide_ adaptive immune system (Fig. 1). It is now widely

accepted that the genome of a common vertebrate ancestor underwent two rounds of WGD, resulting in a fourfold amount of DNA [35]. This increase in accessible raw material made it possible to

refine and diversify the genome. Refinement can be achieved by subfunctionalization, a process by which the functionalities of the original gene are distributed among its daughters, which

can then evolve to become specialized genes [36]. By having multiple copies of the same gene, one of them can be freed from selective pressure and can accumulate mutations, potentially

resulting in new genes with new functions in a process called neofunctionalization, hence diversifying the genome [36]. An immunologically relevant example is the quadruplication of the

proto-major histocompatibility complex (MHC) chromosome that gave rise to four paralogous regions all coding for genes involved in antigen presentation and recognition [37, 38]. In

conclusion, the founding stones for the establishment of an adaptive immune system existed already in primitive bilaterian ancestors, but an enzyme capable of recombination rather than

translocation only occurred in jawed vertebrates. Thus, _bona fide_ adaptive immunity is solely present in gnathostomes and must have appeared first in a common ancestor. THE EVOLUTION OF

IL-4 AND IL-13 Genes encoding for proteins related to signaling in the immune system are under a constant evolutionary pressure to adapt and shape immunity toward the most favorable

protection of the host. This is nicely illustrated by the finding that among the top 25 genes showing the highest degree of evolutionary divergence between mouse and human orthologues, 7

encode for cytokines or cytokine receptors [39]. Due to their low homology even within mammals, the genes encoding for IL-4 and IL-13 are difficult to track in other species. In the

mammalian genome, _Il4_ and _Il13_ are placed side by side and researchers are therefore often searching for both _Il4_- and _Il13_-linked genes as well as flanking genes such as _Kif3a_ and

_Rad50_ that are much better conserved [40]. With the increasing number of genomes being sequenced, a substantial amount of evidence is emerging to shed light on the evolution of these and

other genes. _Il4_/_Il13_-related genes have been found in a number of both fish and bird species and even in amphibians although the latter has not been confirmed by functional studies

(Fig. 1) [40,41,42]. A single _Il4_/_Il13_-related gene was found in spotted gar (_Lepisosteus oculatus_), an example of a bony fish that only went through two rounds of WGD, whereas two

_Il4_/_Il13_-related genes (_Il4/13a_ and _Il4/13b_) have been found in pufferfish (_Tetraodon nigroviridis_) and in zebrafish (_Danio rerio_) as a result of a third round of WGD that

teleost fish went through [43]. Based on these findings, it is believed that a single _Il4_/_Il13_ gene existed in ancestral gnathostomes, which has duplicated during WGD and/or tandem

duplication during vertebrate evolution and thereafter evolved into the so-called type 2 cytokine locus including _Il4_, _Il5_, and _Il13_ [40]. THE EVOLUTION OF THE IL-4 RECEPTOR SYSTEM

IL-4 and IL-13 signal via heterodimeric IL-4Rs composed of three receptor subunits: IL-4Rα, the common gamma chain cytokine receptor (_γ_c), and IL-13Rα1 [8]. IL-4 signals via both the type

1 IL-4R composed of IL-4Rα and _γ_c and the type 2 IL-4R composed of IL-4Rα and IL-13Rα1. IL-13 only signals via the type 2 IL-4R. In addition, IL-13 can interact with IL-13Rα2, which is

thought to be a decoy receptor without signaling function. IL-4R subunits are found in all jawed vertebrates (Fig. 1) [40]. All of the IL-4R and IL-13R genes belong to the class I cytokine

receptors, which most likely originated from glycoprotein 130-like receptors present in invertebrates [44]. Although some class I cytokine receptor genes seem to have arisen from the two

WGD, others have likely been created by tandem or _en bloc_ gene duplication. The extra WGD the teleost lineage went through is possibly responsible for the unique teleost IL-4Rs and

IL-13Rs. There is very sparse information available on cross-reactivity of the IL-4/IL-13–IL-4R system in different species [45]. IL-4Rα (also termed CD124), the shared receptor subunit of

the type 1 and type 2 IL-4Rs, was identified in a large number of sequenced bird genomes [46]. Based on this, the gene was found to have an enhanced rate of nonsynonymous substitutions, and

certain sites were classified as being under particularly high positive selection pressure. Interestingly, this might relate to a finding in the human _Il4ra_ gene where some polymorphisms

led to a higher susceptibility to asthma [47], and in mice where a single amino acid substitution in the _Il4ra_ gene favored the development of asthma-like lung disease [48]. Again, the

fishes undergoing a third round of WGD have two genes encoding for IL-4Rα (IL-4Rα1 and IL-4Rα2), and the _Il4ra_ gene variants differ considerably between species. In zebrafish, alternative

splicing results in a secreted IL-4Rα isoform found in liver, brain, and muscle tissue. Administration of zebrafish recombinant IL-4/13A showed in vivo effects including antibody production

by B cells and CD40 expression, which is important for induction of type 2 immunity [49]. This serves as further proof that a well-developed adaptive immune system is already established in

fishes. _γ_c (also known as CD132, encoded by the _Il2rg_ gene) is a shared receptor subunit of the cytokines IL-2, IL-4, IL-7, IL-9, IL-15, and IL-21 [50]. _Il2rg_ was found in both fishes

and birds. Although the gene in birds is very similar to that of mammals, alternative splice variants exist [51]. _γ_c-expressing T cells in chicken have been shown to be important in

fighting virus infections [52], thus demonstrating a genetic and functional similarity of _γ_c between chickens and humans. In fish, _Il2rg_ was initially identified in rainbow trout

(_Oncorhynchus mykiss)_ and was later found in zebrafish (_Danio rerio_), elephant shark (_Callorhinchus milii_), spotted gar (_Lepisosteus oculatus)_, and in several species of the

_Tilapia_ genus. Similar to _Il4ra_, some fishes have two paralogues of _Il2rg_ [40]. Here, however, the mechanism giving rise to the duplication might not be solely due to a third round of

WGD, as some species have the two genes on the same chromosome. Less research has gone into investigating _Il13ra1_ and _Il13ra2_ (also termed CD213a1 and CD213a2, respectively), but also

these two genes exist in all jawed vertebrates. From a functional perspective, both IL-13Rα1 and IL-13Rα2 are upregulated upon infectious stimuli in chicken [53, 54]. In trout, two

paralogues of both _Il13ra1_ and _Il13ra2_ are present due to a third WGD; whereas the IL-13Rα2-related proteins (IL-13Rα2a/IL-13Rα2b) show 79% amino acid similarity, IL-13Rα1a and IL-13Rα1b

have an amino acid identity of only 34% [55]. A distinctive expression pattern also applies to all of the subunits in trout: thus, IL-13Rα1b and IL-13Rα2b are primarily expressed in the

ovaries, whereas IL-13Rα2a is expressed in spleen, head kidney, and mucosal tissue and IL-13Rα1a in scales, gills, and skin [56]. This suggests that the paralogues specialized to become

tissue-specific. Based on these findings, the expansion and development of the class I cytokine receptors and thereby the IL-4R and IL-13R subunits correlated with the appearance of adaptive

immunity, which occurred together with a refinement of the innate immune system. CONCLUSION Whereas neutrophil-like granular phagocytes were present in invertebrates throughout the

bilaterian clade, we were unable to find data on IL-4, IL-13, IL-4Rα, IL-13Rα1, IL-13Rα2, and _γ_c in invertebrates. Rather, IL-4, IL-13, and their receptors are found in vertebrates, thus

coinciding with the phylogenetic development of a _bona fide_ adaptive immune system. Notably, we did not find any evidence of type 2 cytokines in invertebrates, which could either indicate

that these cytokines evolved later or could be due to a lack of data. The presence of eosinophilic and basophilic granular hemocytes in invertebrates could indicate a primal form of type 2

immunity, possibly harnessing factors that are upregulated during early phases of helminth infestations, such as arginase-1, chitinase-like protein 3, and resistin-like molecule α. However,

how exactly these cells recognize and fight parasites will need to be further investigated. Future studies are necessary to determine whether IL-4R signaling in neutrophils always served a

dual function in adaptive immunity and in curtailing neutrophil effector functions, or whether the neutrophil-specific function of IL-4R signaling evolved later. Moreover, the primary

evolutionary source of IL-4/IL-13 production is still unknown and remains to be assessed in the future. Functional assays in phylogenetically older taxa, such as fishes, are needed to

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expression and modulation. Immunogenetics. 2011;63:235–53. CAS  PubMed  Google Scholar  Download references ACKNOWLEDGEMENTS We would like to thank the current and former members of the

Boyman laboratory for helpful discussions, especially Janine Woytschak and Yulia Butscheid. This work was supported by the Swiss National Science Foundation (310030–172978), the

Hochspezialisierte Medizin Schwerpunkt Immunologie (HSM-2-Immunologie), and the Clinical Research Priority Program CYTIMM-Z of the University of Zurich (all to OB). AUTHOR INFORMATION Author

notes * These authors contributed equally: Lukas E. M. Heeb, Cecilie Egholm AUTHORS AND AFFILIATIONS * Department of Immunology, University Hospital Zurich, CH-8091, Zurich, Switzerland

Lukas E. M. Heeb, Cecilie Egholm & Onur Boyman * Faculty of Medicine, University of Zurich, CH-8006, Zurich, Switzerland Onur Boyman Authors * Lukas E. M. Heeb View author publications

You can also search for this author inPubMed Google Scholar * Cecilie Egholm View author publications You can also search for this author inPubMed Google Scholar * Onur Boyman View author

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ARTICLE Heeb, L.E.M., Egholm, C. & Boyman, O. Evolution and function of interleukin-4 receptor signaling in adaptive immunity and neutrophils. _Genes Immun_ 21, 143–149 (2020).

https://doi.org/10.1038/s41435-020-0095-7 Download citation * Received: 06 December 2019 * Revised: 18 February 2020 * Accepted: 21 February 2020 * Published: 06 March 2020 * Issue Date: May

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