Alternative Activation Is an Innate Response to Injury That Requires CD4+ T Cells to be Sustained during Chronic Infection

Abstract

Alternatively activated macrophages (AAMΦ) are found in abundance during chronic Th2 inflammatory responses to metazoan parasites. Important roles for these macrophages are being defined, particularly in the context of Th2-mediated pathology and fibrosis. However, a full understanding of the requirements for alternative activation, particularly at the innate level, is lacking. We present evidence that alternative activation by the Th2 cytokines IL-4 and IL-13 is an innate and rapid response to tissue injury that takes place even in the absence of an infectious agent. This early response does not require CD4+ Th2 cells because it occurred in RAG-deficient mice. However, class II-restricted CD4+ T cell help is essential to maintain AAMΦ in response to infection, because AAMΦ were absent in RAG-deficient and MHC class II-deficient, but not B cell-deficient mice after chronic exposure to the nematode parasite, Brugia malayi. The absence of AAMΦ was associated with increased neutrophilia and reduced eosinophilia, suggesting that AAMΦ are involved in the clearance of neutrophils as well as the recruitment of eosinophils. Consistent with this hypothesis, AAMΦ show enhanced phagocytosis of apoptotic neutrophils, but not latex beads. Our data demonstrate that alternative activation by type 2 cytokines is an innate response to injury that can occur in the absence of an adaptive response. However, analogous to classical activation by microbial pathogens, Th2 cells are required for maintenance and full activation during the ongoing response to metazoan parasites.

Differential Roles of Macrophages in Diverse Phases of Skin Repair

“…The best characterized activation states in mice encompass classical activated macrophages (also called M1), which exert proinflammatory activities, eradicate invading microorganisms, and promote type I immune responses, and alternatively activated macrophages (also called M2), which are hyporesponsive to proinflammatory stimuli and are involved in debris scavenging, angiogenesis, connective tissue remodeling, and resolution of inflammation (paradigm of M1/M2 polarization) (40). The latter is considered to exert repair and regenerative activities (27,41). However, conclusive evidence as to whether the concept of classical/alternative macrophage activation is operative at the cutaneous wound site and which of the microenvironmental cues might direct macrophage activation is still missing.…”

“…Expression of both factors was recently described as a reliable marker of alternatively activated macrophages (25)(26)(27). Whereas in wound tissue of control mice at day 5 and 10 d postinjury a large fraction of F4/80 + macrophages stained positive for Fizz1, Ym1 was present only until day 5 postinjury (Fig.…”

Dynamics of lung macrophage activation in response to helminth infection

“…Expression profiles of day 2 PI cells isolated from whole lung showed induction of the genes encoding ARG1, FIZZ1, YM1, and AMCase and the lectin MSR1, all hallmark indicators of alternative activation [5]. AAMs are induced by a combination of the rapid induction of Th2 cytokines [13] and tissue injury [51] caused by the Nb larvae as they enter the lungs and then sustained by the long-term changes to the immunological environment of the lung [42].…”

The bright and the dark sides of activin in wound healing and cancer

“…Treatment of mouse macrophages with activin A markedly induced the expression of arginase-1 (Ogawa et al, 2006), a marker for M2 macrophages that are involved in tissue repair processes (Loke et al, 2007) (see glossary in Box 1). By contrast, it decreased the interferon (IFN)-c-induced expression of inducible nitric oxide (NO) synthase, which is a marker for inflammatory M1 macrophages (Ogawa et al, 2006).…”