The host immune response to infectious challenge affords multiple potential signals for BMSC activation. TLRs recognize PAMPs and DAMPs within the microenvironment. The microenvironment milieu is the composite of resident and immigrating hematopoietic and nonhematopoietic cells responding to pathogen and the associated constitutive and inducible soluble factors that these cells produce. During infectious challenge, TLR ligands activate immune effector cells, such as DCs, monocytes, and macrophages (Mo/Mφ), and T cells to produce pro-inflammatory cytokines and chemokines. These soluble factors in turn activate additional host defense responses, including recruitment of immune effector cells (chemotaxis gradient). Pathogen is eliminated directly through immune effector cells themselves (eg, phagocytosis) and by the antimicrobial soluble factors they produce (eg, TNF-α and IFN-γ). Resultant pathogen cell necrosis and tissue toxicity release additional DAMPs, which accumulate and form pro-inflammatory damage and oxygen stress gradients. To preserve host integrity, regulatory hematopoietic cells, also activated by PAMPs and DAMPs, function to counter inflammation through the production of anti-inflammatory and antioxidant paracrine soluble factors. BMSCs possess TLRs, which could potentially recognize pathogen and danger signals and activate BMSCs to function as nonhematopoietic immunomodulatory cells during infection. Block arrows (≫) indicate potential influences within each phase of host response to infection that may influence BMSC activation and function. Further investigation is needed to confirm these putative signals.