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Low oxygen tension occurs virtually in every site of inflammation, necrotic foci, infection, and wounding. It has become widely recognized that the dynamic interaction between multiple cellular components of damaged tissues, including but not limited to immune and stromal inflammatory cells, and microenvironmental factors, for example, hypoxia, plays a critical role in the pathophysiology of human diseases ranging from infections to chronic inflammation to cancer. Hypoxia modulates leukocyte functions, including migration and survival, by reprogramming the immune responses in pathologic tissues and promoting the innate immune functions of neutrophils, macrophages, and dendritic cells to the disadvantage of adaptive immunity. Strikingly, hypoxia and inflammatory signals share selected transcriptional events, including the activation of members of both the hypoxia-inducible factor and nuclear factor κB families, which may converge to activate specific cell programs. Here, we review the mechanisms of innate immunity adaptation to hypoxia, their role in disease, as well as new perspectives for their therapeutic targeting.

Innate immunity has an adaptive component, which has been referred to as "memory," "trained," "imprinted" or "adaptive." Plasticity is a hallmark of cells of the monocyte-macrophage lineage. Microbial recognition and cytokines profoundly affect macrophage function causing a range of adaptive responses including activation, priming, or tolerance. These adaptive responses of macrophages include production of humoral fluid-phase pattern recognition molecules such as the prototypic long pentraxin PTX3. These components of humoral innate immunity in turn cooperate with and regulate phagocyte function. Progress has been made in defining the molecular basis underlying the polarized activation of macrophages, including signaling mediators, transcription factors, epigenetic modifications, and the microRNA network. The definition of molecules and mechanisms associated with plasticity and polarized activation of macrophages may provide a basis for innovative diagnostic and therapeutic approaches.

Publisher Summary This chapter reviews the key properties of tumor-associated macrophages (TAMs), emphasizing on the genetic evidence and the emerging targets for therapeutic intervention. TAMs derive from the circulating monocytes and are recruited at the tumor site by a tumor-derived chemotactic factor for monocytes. TAMs that have immunoregulatory and immunosuppressive activity produce growth factors that stimulate angiogenesis, remodel tissues, and facilitate invasion and metastasis. TAMs and the related immature myeloid suppressor cells have the properties of M2 macrophage populations that are supportive to tumors. In many human tumors, a high frequency of infiltrating TAMs is associated with poor prognosis. TAMs participate in the proangiogenic process by producing the angiogenic factor thymidine phosphorylase (TP), which promotes the endothelial cell migration in vitro and whose levels of expression are associated with tumor neovascularization. TAMs contribute to tumor progression also by producing proangiogenic and tumor-inducing chemokines, such as CCL2. Moreover, TAMs accumulate in the hypoxic regions of tumors, and hypoxia triggers a proangiogenic program in these cells.