Recruitment of hepatic macrophages from monocytes is independent of IL‐4Rα but is associated with ablation of resident macrophages in schistosomiasis

Abstract

Alternatively activated Mϕs (AAMϕ) accumulate in hepatic granulomas during schistosomiasis and have been suggested to originate in the bone marrow. What is less understood is how these Mϕ responses are regulated after S. mansoni infection. Here, we investigated the role of IL-4 receptor α-chain (IL-4Rα)-signalling in the dynamics of liver Mϕ responses. We observed that IL-4Rα signalling was dispensable for the recruitment of Ly6C hi monocytes and for their conversion into F4/80 hi CD64 hi CD11b hi Mϕ. Moreover, while IL-4Rα provided an AAMϕ phenotype to liver F4/80 hi CD64 hi CD11b hi Mϕ that was associated with regulation of granuloma formation, it was dispensable for host survival. Resident F4/80 hi CD64 hi CD11b lo Mϕ did not upregulate the AAMϕ signature gene Ym1. Rather, resident Mϕ nearly disappeared by week 8 after infection and artificial ablation of resident Mϕ in CD169 DTR mice did not affect the response to S. mansoni infection. Interestingly, ablation of CD169 + cells in naive mice resulted in the accumulation of F4/80 hi CD64 hi CD11b hi Mϕ, which was amplified when ablation occurred during schistosomiasis. Altogether, our results suggest the ablation of resident KCs after S. mansoni infection to be associated with the recruitment and accumulation of F4/80 hi CD64 hi CD11b hi Mϕ with lyz2-dependent IL-4Rα contributing to the regulation of granuloma inflammation but being dispensable for host survival.Keywords: liver r monocytes r mouse model r Mϕ r schistosomiasis See accompanying Commentary by Rückerl and CookAdditional supporting information may be found online in the Supporting Information section at the end of the article. infected with Schistosoma mansoni develop a severe liver pathology with granulomatous inflammatory responses directed toward the parasite eggs. During chronic infections, type 2 inflammation in the liver results in fibrosis, which leads to portal hypertension, bleeding from collateral vessels and ultimately death [2][3][4]. Mϕ accumulate in the liver and are a key cellular component in granuloma formation and host protection [2,5].Mϕ are plastic cells that can be alternatively activated by IL-4 and IL-13 via the type I or type II IL-4 receptor, respectively [6].

Macrophages assemble! But do they need IL‐4R during schistosomiasis?

“…conclude from their data that Mres have no role in the resistance to S. mansoni infection. However, it has to be noted, as also shown by the authors, that Mres have a clear anti‐inflammatory role, limiting the influx of neutrophils and monocytes and regulating the silent removal of apoptotic cells under steady state . Thus, although the authors did not observe any effects of Mres depletion on survival in their model, Mres may play an important role in avoiding immunopathology in chronic human infections, or may be a deciding factor distinguishing patients who develop symptoms of the disease or stay asymptomatic .…”

“…turned their attention to the role of Mres in the resistance to S. mansoni infection. Their data showed a marked loss in the number of these cells over the course of the infection as well as rather limited induction of M(IL‐4) markers (Fig ) . This indicated that Mres might not be involved in the immune response against S. mansoni .…”

“…now show that the influx of blood monocytes and their conversion to macrophages in the liver is completely independent of IL‐4Rα expression by macrophages (Fig ). Indeed, the authors found limited evidence that proliferative expansion in general, let alone driven by IL‐4, contributes to the number of macrophages present in the liver at any stage during the infection . Thus, despite the prevalent type 2 environment during S. mansoni infection, IL‐4Rα mediated signals do not appear to be involved in the expansion/recruitment of macrophages in the liver.…”

“…This indicated that Mres might not be involved in the immune response against S. mansoni . Indeed, depletion of liver Mres using a CD169‐DTR model resulted in unaltered survival and granuloma formation as well as largely unchanged cellular infiltration to the liver . This is not limited to the liver, as it has been recently demonstrated that alveolar macrophages (i.e.…”

“…found heightened liver granuloma pathology, but not mortality, in infected IL‐4Rα flox/− LysM Cre mice. Simultaneously, M(IL‐4) activation was strongly diminished, albeit not completely abolished . This raises the question whether M(IL‐4) activity is indeed important for wound healing during S. mansoni infection.…”