M2-like, dermal macrophages are maintained via IL-4/CCL24–mediated cooperative interaction with eosinophils in cutaneous leishmaniasis

Abstract

Tissue-resident macrophages (TRMs) maintain tissue homeostasis, but they can also provide a replicative niche for intracellular pathogens such as Leishmania. How dermal TRMs proliferate and maintain their M2 properties even in the strong TH1 environment of the L. major infected dermis is not clear. Here, we show that, in infected mice lacking IL-4/13 from eosinophils, dermal TRMs shifted to a proinflammatory state, their numbers declined, and disease was attenuated. Intravital microscopy revealed a rapid infiltration of eosinophils followed by their tight interaction with dermal TRMs. IL-4–stimulated dermal TRMs, in concert with IL-10, produced a large amount of CCL24, which functioned to amplify eosinophil influx and their interaction with dermal TRMs. An intraperitoneal helminth infection model also demonstrated a requirement for eosinophil-derived IL-4 to maintain tissue macrophages through a CCL24-mediated amplification loop. CCL24 secretion was confined to resident macrophages in other tissues, implicating eosinophil-TRM cooperative interactions in diverse inflammatory settings.

Macrophages and the maintenance of homeostasis

“…[28][29][30] This is an attractive idea that is consistent with some good experimental data. 29,[31][32][33] However, this idea is inconsistent with what we consider to be a fundamental property of macrophages, which is plasticity. All macrophages, including tissue-resident cells, express pattern recognition receptors that allow them to respond to activating stimuli.…”

Adult‐onset eosinophilic airway diseases

“…Eosinophils can be a rich source of type 2 cytokines; two recent reports using mice in different disease settings have demonstrated the pathological importance of eosinophil-derived IL-4. 31,32 Chronic tissue eosinophilia initiate tissue remodelling through their secretory products, including VEGF, TGFβ and profibrotic osteopontin. 11,33,34 In a cohort of moderate persistent asthmatics, blood eosinophil count and F I G U R E 2 Eosinophil-mediated chronic airway inflammation.…”

Immunometabolism of Leishmania granulomas

“…M2 macrophages can be maintained under these circumstances by local feedback loops involving IL-4-producing eosinophils and/or excessive local production of NO which suppresses macrophage inflammatory responses. 8,14 These feedback loops, together with gradients in nutrients, oxygen and other factors, may lead to substantial heterogeneity in the types of host cell that are infected, as well as their replicative potential and state of polarization. Figure 1.…”

“…Infected apoptotic neutrophils and/or released parasites are subsequently taken up by tissue‐resident macrophages (dermal macrophages in the skin and Kupffer cells in liver) and dendritic cells, which triggers the differentiation of internalized parasites into obligate intracellular amastigotes within the parasitophorous vacuole (PV) of these host cells 5 . Further recruitment of monocytes and other immune cells leads to the development of granulomatous lesions in the skin composed of infected and uninfected macrophages, monocytes and dendritic cells, as well as a significant number of neutrophils (that can also be infected) and eosinophils 6–8 (Figure 1a). Expansion of the granuloma occurs through the interferon‐γ (IFNγ)‐mediated recruitment of inflammatory monocytes that rapidly outnumber tissue macrophages and actively phagocytose dying infected host cells, promoting parasite transmission between monocytes and macrophages in the lesions 9–11 (Figure 1a).…”

“…While this paradigm is supported by many studies, recent work has shown that Leishmania granulomas can contain subpopulations of macrophages in both M1‐ and M2‐polarized states even when a strong host‐protective T‐helper type 1 response is induced 13 (Figure 1a). M2 macrophages can be maintained under these circumstances by local feedback loops involving IL‐4‐producing eosinophils and/or excessive local production of NO which suppresses macrophage inflammatory responses 8,14 . These feedback loops, together with gradients in nutrients, oxygen and other factors, may lead to substantial heterogeneity in the types of host cell that are infected, as well as their replicative potential and state of polarization.…”