Jenkins SJ, Ruckerl D, Cook PC, Jones LH, Finkelman FD, van Rooijen N, et al. Local macrophage proliferation, rather than recruitment from the blood, is a signature of Th2 inflammation. Science 2011;332: 1284-1288. (Reprinted with Permission.)
A defining feature of inflammation is the accumulation of innate immune cells in the tissue that are thought to be recruited from the blood. We reveal that a distinct process exists in which tissue macrophages undergo rapid in situ proliferation in order to increase population density. This inflammatory mechanism occurred during T helper 2 (TH2)-related pathologies under the control of the archetypal TH2 cytokine interleukin-4 (IL-4) and was a fundamental component of TH2 inflammation because exogenous IL-4 was sufficient to drive accumulation of tissue macrophages through self-renewal. Thus, expansion of innate cells necessary for pathogen control or wound repair can occur without recruitment of potentially tissue-destructive inflammatory cells. (HEPATOLOGY 2011)
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A defining feature of inflammation is the accumulation of innate immune cells in the tissue that are thought to be recruited from the blood. We reveal that a distinct process exists in which tissue macrophages undergo rapid in situ proliferation in order to increase population density. This inflammatory mechanism occurred during T helper 2 (TH2)-related pathologies under the control of the archetypal TH2 cytokine interleukin-4 (IL-4) and was a fundamental component of TH2 inflammation because exogenous IL-4 was sufficient to drive accumulation of tissue macrophages through self-renewal. Thus, expansion of innate cells necessary for pathogen control or wound repair can occur without recruitment of potentially tissue-destructive inflammatory cells.
Kupffer cells, local macrophages residing within the liver sinusoids, have long been identified as key components in almost all scenarios of liver injury and inflammation. Though they partake in the clearance of food-derived antigens from the portal vein and provide anti-inflammatory signals during homeostasis, they are rapidly activated upon hepatic injury, phagocytize pathogens, and release many cytokines and chemokines that subsequently promote inflammatory responses in the liver.1 Over recent years, several studies in mice have emphasized that many of the crucial functions of hepatic macrophages are not primarily exerted by resident Kupffer cells, but by other macrophages derived from infiltrating monocytes. Even in steady-state conditions, the Kupffer cell pool is apparently constantly replenished by monocyte-derived macrophages.1, 2 Upon acute or chronic liver injury, a great number of monocytes infiltrate the liver after chemokine signals provided by resident macrophages, stellate cells, hepatocytes, or endothelial cells, including CCR2/CCL2 and CX3CR1/CX3CL1.3-6 Studies in mice with chronic liver damage and induction of liver fibrosis have revealed that monocyte-derived macrophages can release several cytokines that perpetuate chronic inflammation as well as directly activate hepatic stellate cells (HSCs), which, in turn, proliferate and transdifferentiate into collagen-producing myofibroblasts (Fig. 1). However, macrophages are also important for the resolution of hepatic inflammation and fibrosis, because they can provide anti-inflammatory cytokines and degrade extracellular matrix.7, 8 Several therapeutic approaches, including pharmacological inhibition of monocyte migration or the intravenous transfer of macrophages, have been evaluated in animal models and are currently being translated into initial clinical trials.9, 10 These therapeutic opportunities emphasize the exceptional importance of understanding the exact pathways of macrophage activation and functionality in the liver, as well as the distinct contribution of infiltrating and resident macrophages to hepatic inflammation.
In principal, macrophages have been divided into classically (CAM; often also termed M1) and alternatively activated macrophages (AAM; also termed M2), with the former being important in antibacterial defense and support of Th1-type T helper cells and the latter rather contributing to antiparasite defense, Th2 T-cell support, and wound healing, but also to fibrotic processes in chronic inflammation and tumor growth.11, 12 Such pathological functions make AAMs promising candidates for antifibrotic and -tumor therapies. Many of these therapies use the strategy of preventing the recruitment of monocyte precursors of macrophages, for example, by blocking the chemokines that attract these cells. In a recent publication in Science, Judith Allen's group now suggests that this strategy may not work in conditions where AAMs are to be targeted.13
Jenkins et al. studied murine models of distinct experimental conditions, in which AAMs play a dominant role, namely parasite infections and sterile inflammation of the peritoneal cavity. They noted that depletion of monocyte precursors prevented the accumulation of CAMs, but not of AAMs. Furthermore, they found that AAMs undergo intense local proliferation, in contrast to CAMs. This local AAM proliferation was driven by interleukin-4 (IL-4), the master Th2 cytokine. Moreover, IL-4-driven proliferation was important for the self-renewal of tissue-resident macrophages in many tissues, including the liver (Fig. 1). These findings indicate that macrophages involved in Th1 or Th2 inflammation may respond in a fundamentally different manner. CAMs perform a rapid response suitable to destroy pathogens, whereas the slower local expansion of AAMs appears most suitable for tissue-repair processes and wound healing.13
These conclusions challenge the current dogma that inflammatory macrophages are always recruited to sites of inflammation or infection.14 Apart from advancing our basic understanding of macrophage biology, these discoveries may also have profound clinical implications, because therapeutic strategies against tumors and fibrosis have to be reevaluated. In particular, IL-4 emerges as an interesting target for these aims. However, it has to be kept in mind that the models studied in this article are very unique, because they are extremely skewed toward AAM/Th2-type responses. By contrast, classical experimental models of chronic liver injury as well as human liver diseases are more heterogeneous, because disease progression typically involves CAM- and Th1-polarized actions, and inflammatory monocytes/macrophages (likely CAMs) can directly activate fibrogenesis.1, 3, 15 In fact, local proliferation of Kupffer cells has not been reported on from typical chronic injury or fibrosis models, as yet.4 With respect to the resolution of hepatic inflammation and fibrosis, it will be important to clarify the extent by which locally proliferating Kupffer cells and/or the reprogramming of infiltrated monocyte-derived macrophages contribute to the anti-inflammatory cytokine milieu, tissue repair, and matrix degradation.8 Thus, further studies are required to ascertain whether these findings in mouse models of parasite and sterile peritonitis have revealed mechanisms that pertain also to clinically relevant tumors or liver diseases leading to hepatic inflammation and fibrosis.
The authors thank Thomas Ritz and Matthias Bartneck (both from F.T.'s group) for providing experimental data used in Fig. 1B and John P. Iredale (University of Edinburgh, Edinburgh, Scotland, UK) for his helpful discussions.