Introduction: Platelets are an important part of the immune system. Platelets regulate both innate and adaptive immune responses: platelets activate the acute phase response, release cytokines and chemokines that recruit and activate immune cells, and platelets present antigen through major histocompatibility complex I (MHCI). Beta-2 microglobulin (β2M) is the chaperone protein for the MHCI complex, but β2M is non-covalently bound to MHCI and is shed into the plasma. β2M is the most abundant transcript in platelets and is stored and released from platelet granules. β2M has been used as a biomarker of inflammatory diseases and elevated levels of plasma β2M are found in tuberculosis, myeloma, malaria, and HIV, among many diseases. We propose that platelet derived β2M is more than a biomarker and directly drives inflammatory disease by inducing pro-inflammatory monocyte responses.
Results: Primary mouse monocytes cultured in the presence of exogenous β2M, time and dose dependently, promoted a pro-inflammatory phenotype as indicated by increased surface CD11b and Ly6C expression as well as the release of KC/CXCL1 and IL-6. Similarly, treatment of human monocytes with exogenous β2M induced a monocyte pro-inflammatory phenotype by increased CD16 expression and release of IL-8 and IL-6, but not IL-10. To explore the role of platelet β2M in vivo we generated platelet specific β2M-/- mice (PF4-Cre-β2Mflox/flox). These mice had greatly reduced plasma β2M demonstrating that platelets are a major source of plasma β2M. Monocytes have a major role in myocardial infarction (MI) immune responses. WT or β2M-/- mice therefore had their left anterior descending artery (LAD) ligated and monocyte responses determined. WT mice had significantly more post-MI circulating Ly6Chi monocytes and plasma KC compared to β2M-/- mice on d3 and 7 post-MI. β2M-/- mice had fewer inflammatory cell infiltrates, but more evidence of cardiac fibrosis and a greater decline in heart function on d15 post-MI compared to WT mice.
Conclusions: These data demonstrate that platelets are major regulators of monocyte inflammatory responses via the abundant platelet derived molecule β2M. This provides a highly novel and physiologically relevant role for β2M beyond its role as molecular chaperone.