g. TNFα and IL-1β) and chemoattractants, thereby recruiting macrophages into damaged areas in order to resolve the injury

(see Figure 1) [7]. Thus, soluble biglycan acts as a danger signal, which initiates a rapid innate immune response without the need for de novo synthesis of ‘warning’ molecules. this website In addition, upon stimulation with proinflammatory cytokines, resident cells and infiltrating macrophages synthesize full-length biglycan leading to the recruitment of additional macrophages, which are also capable of synthesizing and secreting biglycan [ 7]. This creates a feed-forward loop that leads to robust proinflammatory signaling. Moreover, biglycan is capable of clustering TLR2/4 with purinergic P2X7 receptors, thereby autonomously activating the NLRP3 inflammasome and caspase-1 and secretion of mature IL-1β (see Figure 1) [ 8]. Besides recruiting macrophages, biglycan stimulates the TLR2/4-dependent synthesis of key chemoattractants

for OSI-906 clinical trial T and B lymphocytes and is thus also involved in the adaptive immune response (see Figure 1). Biglycan specifically recruits B1 lymphocytes which are responsible for T cell-independent production of antibodies. This represents an early defense against pathogens, before the adaptive immune response is activated. The biological importance of these mechanisms has been shown in systemic lupus erythematosus (SLE), a prototypic autoimmune disease affecting mainly young women. In SLE, soluble biglycan stimulates the synthesis of autoantibodies and enhances recruitment of macrophages as well as T and B lymphocytes resulting in enhanced inflammation in target organs. Notably, biglycan attracts B cells to chronically inflamed non-lymphoid organs and promotes the Amino acid development of tertiary lymphoid tissue and acceleration of disease [9]. Collectively, these findings shed new light on the mechanisms of sterile inflammation, which plays a key role in tissue repair

and regeneration (e.g., wound healing), ischemia/reperfusion injury (e.g., myocardial infarction) and autoimmune diseases (e.g., rheumatoid arthritis, SLE) among others. There is emerging evidence that soluble biglycan is generated in non-pathogen-mediated inflammatory diseases and autonomously triggers sterile inflammation by orchestrating TLR2/4 and NLRP3 inflammasome signaling [9]. On the other hand, in pathogen-mediated inflammation, the affinity of biglycan to receptors sensing either gram-positive or gram-negative pathogens allows for enhancement of inflammation via a second TLR, which is not involved in pathogen sensing [10]. The SLRPs are emerging as powerful signaling molecules affecting both cancer growth and inflammation. Thus, because cancer and inflammation are closely linked, we envisage that SLRPs such as decorin and biglycan could potentially become valid natural therapeutic agents or target themselves.