Monocytes in sterile inflammation: recruitment and functional consequences

Abstract

Monocytes play an important role in initiating innate immune responses. Three subsets of these cells have been defined in mice including classical, nonclassical and intermediate monocytes. Each of these cell types has been extensively studied for their role in infectious diseases. However, their role in sterile injury as occurs during ischemia-reperfusion injury, atherosclerosis, and trauma has only recently been the focus of investigations. Here, we review mechanisms of monocyte recruitment to sites of sterile injury, their modes of action, and their effect on disease outcome in murine models with some references to human studies. Therapeutic strategies to target these cells must be developed with caution since each monocyte subset is capable of mediating either anti- or pro-inflammatory effects depending on the setting.

Figure 1

Two distinct subtypes of murine monocytes exist, nonclassical (Ly6C^loCCR2^loCD43^hiCX₃CR1^hiCD11b^hi) and classical (Ly6C^hiCCR2^hiCD43^intCX₃CR₁^intCD11b^hi). The nonclassical subset originates in the bone marrow and is recruited to sites of inflammation by CCR5 ligands. Classical monocytes reside in the bone marrow, but also have a reservoir in the spleen. Egress from the bone marrow is dependent on CCR2 ligands, while migration out of the spleen is dependent on Angiotensin II. Upon entering the bloodstream, they are recruited to sites of inflammation through CCL2, CX₃CL1, and CCR5 ligands. While nonclassical monocytes play an important role in the resolution of inflammation and secreting VEGF and other pro-angiogenic factors, classical monocytes increase production of pro-inflammatory cytokines and chemokines, cause neutrophil recruitment, lead to an increase in proteinase activity, and can also resolve inflammation.