Alternative Macrophage Activation Is Essential for Survival during Schistosomiasis and Downmodulates T Helper 1 Responses and Immunopathology

Abstract

Macrophage/neutrophil-specific IL-4 receptor alpha-deficient mice (LysM(Cre)IL-4Ralpha(-/flox)) were generated to understand the role of IL-4/IL-13 responsive myeloid cells during Type 2 immune responses. LysM(Cre)IL-4Ralpha(-/flox) mice developed protective immunity against Nippostrongylus brasiliensis accompanied by T(H)2 development and goblet cell hyperplasia. In contrast, LysM(Cre)IL-4Ralpha(-/flox) mice were extremely susceptible to Schistosoma mansoni infection with 100% mortality during acute infection. Mortality was not dependent on neutrophils and occurred in the presence of T(H)2/Type 2 responses, granuloma formation, and egg-induced fibrosis. Death was associated with increased T(H)1 cytokines, hepatic and intestinal histopathology, increased NOS-2 activity, impaired egg expulsion, and sepsis. IL-10 was not able to compensate for the absence of IL-4/IL-13-activated alternative macrophages. Together, this shows that alternative macrophages are essential during schistosomiasis for protection against organ injury through downregulation of egg-induced inflammation.

Helminth-Induced Interleukin-4 Abrogates Invariant Natural Killer T Cell Activation-Associated Clearance of Bacterial Infection

“…Additionally, the ability of IL-4-neutralizing antibody to restore baseline resistance to prolonged bacteriuria in coexposed mice also argues for a predominant role for IL-4. It has been shown that a lack of IL-4R␣ signaling in S. mansoni-infected mice results in a compensatory, rigorous IFN-␥ response (22). However, we did not observe this type of response in coexposed IL-4R␣ Ϫ/Ϫ mice, effectively excluding the possibility that the recovery of resistance to bacteriuria in these mice was simply due to an increase in the type 1 immune response.…”

“…Exaggerated IFN-␥ responses have been observed in IL-4R␣ Ϫ/Ϫ mice infected with Schistosoma mansoni or Nippostrongylus brasiliensis (22). To rule out the possibility that our observations derived from IL-4R␣ Ϫ/Ϫ mice were due simply to increased IFN-␥ production, bladder cytokine expression levels were compared between coexposed IL-4R␣ Ϫ/Ϫ mice and wild-type mice.…”

Interleukin-13 (IL-13)/IL-13 Receptor α1 (IL-13Rα1) Signaling Regulates Intestinal Epithelial Cystic Fibrosis Transmembrane Conductance Regulator Channel-dependent Cl− Secretion

“…IL-4/IL-13 stimulate isotype switching to IgE, mast cell development, increased sensitivity to mast cell-produced mediators, generation of M2 macrophages, goblet cell hyperplasia, RELM␤ production, epithelial proliferation, and shedding of intraepithelial cells, intestinal smooth muscle contractility, and paracellular permeability (8,27,45,(57)(58)(59)(60)(61). IL-13 regulation of CFTR Cl Ϫ channel expression and Cl Ϫ secretion driving mucosal hydration and secretory diarrhea would be consistent with these functions.…”

Protein kinase C δ is essential for optimal macrophage-mediated phagosomal containment ofListeria monocytogenes

“…Liver and spleen sections were stained with hematoxylin and eosin, and the number and size of 80 liver microabscesses per mouse per group were measured as described (43).…”

“…Quantitative RT-PCR was performed as described (43) by using primers for PKC␦ (forward, 5Ј-CGG GCT ACG TTT TAT GC-3Ј; reverse, 5Ј-TCC AAC GGG GAT AG TG-3Ј), IL-6 (forward, 5Ј-GTT CTC TGG GAA ATC GTG GA-3Ј; reverse, 5Ј-TGT ACT CCA GGT AGC TAT GG-3Ј), NF-IL6 (forward, 5Ј-CCC ATG GAA GTG GCC AAC T-3Ј; reverse, 5Ј-GCG AAG AGG TCG GAG AGG AA-3Ј), and ␤2-microglobulin (forward, 5Ј-TGA CCG GCT TGT ATG CTA TC-3Ј; reverse, 5Ј-CAG TGT GAG CCA GGA TAT AG-3Ј). Relative mRNA expression values were calculated by dividing the calculated value for the gene of interest by the ␤2-microglobulin value.…”