Human intestinal macrophages display profound inflammatory anergy despite avid phagocytic and bacteriocidal activity

Abstract

Intestinal macrophages, which are thought to orchestrate mucosal inflammatory responses, have received little investigative attention compared with macrophages from other tissues. Here we show that human intestinal macrophages do not express innate response receptors, including the receptors for LPS (CD14), Fcα (CD89), Fcγ (CD64, CD32, CD16), CR3 (CD11b/CD18), and CR4 (CD11c/CD18); the growth factor receptors IL-2 (CD25) and IL-3 (CD123); and the integrin LFA-1 (CD11a/CD18). Moreover, resident intestinal macrophages also do not produce proinflammatory cytokines, including IL-1, IL-6, IL-10, IL-12, RANTES, TGF-β, and TNF-α, in response to an array of inflammatory stimuli but retain avid phagocytic and bacteriocidal activity. Thus, intestinal macrophages are markedly distinct in phenotype and function from blood monocytes, although intestinal macrophages are derived from blood monocytes. To explain this paradox, we show that intestinal stromal cell-derived products downregulate both monocyte receptor expression and, via TGF-β, cytokine production but not phagocytic or bacteriocidal activity, eliciting the phenotype and functional profile of intestinal macrophages. These findings indicate a mechanism in which blood monocytes recruited to the intestinal mucosa retain avid scavenger and host defense functions but acquire profound "inflammatory anergy," thereby promoting the absence of inflammation characteristic of normal intestinal mucosa despite the close proximity of immunostimulatory bacteria.

Macrophages Are Phenotypically and Functionally Diverse across Tissues in Simian Immunodeficiency Virus-Infected and Uninfected Asian Macaques

“…In addition to maintaining a larger frequency of macrophages, colonic macrophages were significantly more functional than jejunal macrophages, with higher frequencies secreting IL-1␤ and IL-6. Although these results contrast with previous findings describing a largely anti-inflammatory function for intestinal macrophages (30,36,47), our findings do not preclude the presence of balanced immunoregulatory responses by macrophages or by other regulatory cells in culture and in vivo. Of interest, we observed a significant difference in the functional response of colonic macrophages to stimulation with BS-PGN compared to the same stimulation of macrophages in other anatomic sites.…”

The Innate Immune System: A Trigger for Many Chronic Inflammatory Intestinal Diseases

“…They display a specific phenotype with low expression of monocyte antigens such as CD14 or CD16 [21] and with low expression of co-stimulatory molecules such as CD80 or CD86 or pattern recognition receptors such as TLR4 or TLR2 [20,37]. In contrast to blood monocytes or in vitro-differentiated macrophages, normal intestinal macrophages are rather irresponsive to lipopolysaccharide [37,38,39]. On the other hand, the phenotype and the functional characteristics of intestinal macrophages are altered during chronic inflammation in IBD.…”

Innate and Adaptive Immunity in Inflammatory Bowel Diseases

“…Intestinal macrophages are characterized by the markers F4/80, CD115 and CD14, but lack CD103 expression [10]. It has been shown that under healthy conditions, intestinal macrophages show profound anergy and contribute to tissue homeostasis through downregulation of proinflammatory cytokines [11,12]. This attenuation mediates physiologic tolerance.…”