Fig. 2.

Different therapeutic strategies to control the inflammatory activity of monocytes based on a mouse model. During infection and chronic inflammation, Ly6C^high monocytes that derived from granulocyte-monocyte progenitor (GMPs), monocyte-dendritic cell progenitor (MDP) and common monocyte progenitor (cMoP), egress from the bone marrow and selectively traffic to sites of inflammation. The Ly6C^high monocyte egression requires expression of the chemokine receptor CCR2. The migration of Ly6C^high monocyte to tissue where they can retain their own properties without differentiating into macrophage or dendritic cell is prominent and robust. Ly6C^high monocytes can theoretically convert into Ly6C^low cells although this is debatable due to the possible existence of Ly6C^low progenitors not yet identified [68]. When the antiinflammatory activity of Ly6C^low monocytes is not able to counteract the inflammatory mediator release, the inflammatory state persists causing tissue damage. In this context, a therapeutic intervention is necessary to return to homeostasis. a One strategy may consist in the manipulation of the hematopoietic stem cell (HSC) development by systemic administration of TLR agonist (alone or in association) that may change the ratio Ly6C^high versus Ly6C^low monocyte number by promoting the expansion, egress, and activation of Ly6C^low monocytes. b The second strategy is based on the differential use of signalling pathways by monocyte subpopulations according to Gravina et al. [41] allowing to specifically target inflammatory monocytes. In a context where proinflammatory cytokines are released by Ly6C^high monocytes in a MyD88/IRAK4-dependent way and antiinflammatory cytokines are produced by Ly6C^low monocyte in a Mal/TIRAP- dependent way, IRAK4 inhibitors appear relevant to treat exacerbated inflammatory disorders. This may allow to specifically reduce inflammatory mediators released by Ly6C^high monocytes without altering repair functions of other monocyte populations