Human STAT6 blocking peptide

Alternatively activated macrophages (AAMs) can contribute to wound healing, regulation of glucose and fat metabolism, resolution of inflammation, and protective immunity against helminths. Their differentiation, tissue distribution, and effector functions are incompletely understood. Murine AAMs express high levels of resistin-like molecule (RELM) alpha, an effector protein with potent immunomodulatory functions. To visualize RELM alpha(+) macrophages (M Phi s) in vivo and evaluate their role in defense against helminths, we generated RELM alpha reporter/deleter mice. Infection with the helminth Nippostrongylus brasiliensis induced expansion of RELM alpha(+) lung interstitial but not alveolar M Phi s in a STAT6-dependent manner. RELM alpha(+) M Phi s were required for prevention of fatal lung damage during primary infection. Furthermore, protective immunity was lost upon specific deletion of RELM alpha(+) M Phi s during secondary infection. Thus, RELM alpha reporter/deleter mice reveal compartmentalization of AAMs in different tissues and demonstrate their critical role in resolution of severe lung inflammation and protection against migrating helminths.

Intestinal epithelial cells (IECs) constitute an important barrier between host and pathogen. Immune mechanisms that provide protection against gastrointestinal helminths often require IL-4R alpha-induced activation of STAT6-regulated genes in IECs. However, it is not known whether STAT6 activation in IECs enhances protective immunity against helminths. Furthermore, the regulation of proliferation and differentiation processes of the intestinal epithelium by IEC-intrinsic STAT6 signaling remains unclear. To address these questions, we generated mice with specific expression of a constitutively active version of STAT6 in IECs. These VillinCre_STAT6vt mice show accumulation of secretory IECs, increased proliferation of IECs and lengthening of the small intestine. They rapidly expelled Nippostrongylus brasiliensis worms even in the absence of T cells. Furthermore, primary infection with Heligmosomoides polygyrus resulted in larval trapping in the submucosa and the fecundity of adult worms was severely impaired. Our results reveal an important IEC-intrinsic role of STAT6-regulated genes for intestinal homeostasis and protective immunity against helminths.