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Microbes & Immunity Role of SRCR proteins in inflammation

CD5L may indeed surpass its antimicrobial effects, offering Like CD5L, CD6 has also been utilized in therapeutic
promising opportunities for therapeutic applications. animal models of sepsis with relative success. Although
the effects of extracellular rCD6 have not been evaluated
3. Cell-surface SRCRs and their cleavage when administered concurrently with CLP induction, it
products shows effectiveness when given 1 h after induction onset.
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While soluble SRCR proteins play pivotal roles in microbial However, its efficacy declines if administered later (at 3 or
recognition and anti-inflammatory responses, cell-surface 6 h), resulting in generally less favorable outcomes. This
receptors such as CD5, CD6, CD163, and CD163 antigen- highlights the critical importance of timing in therapeutic
interventions.
like 1 (CD163L1) offer a contrasting yet complementary
function. These receptors, primarily located on immune CD163, predominantly expressed on macrophages and
cells, exhibit unique dynamics in their engagement with monocytes, functions as an anti-inflammatory receptor
microbial components. While their direct microbial that scavenges haptoglobin-hemoglobin complexes and
recognition is less pronounced than soluble SRCRs, interacts with various pathogens, including viruses and
especially for T-cell antigens such as CD5 and CD6, 4,5,21 bacteria. Its expression is upregulated by glucocorticoids
their significance emerges when proteolytic cleavage and anti-inflammatory cytokines such as IL-10, whereas
occurs during infections or inflammation. pro-inflammatory signals such as TNF-α and interferon-
gamma (IFN-γ) can lead to its suppression. Proteolytic
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CD5 is a transmembrane protein primarily expressed
in mature T cells and a subset of B cells, characterized by shedding of CD163 releases soluble CD163 (sCD163),
which influences immune responses and is elevated in
three consecutive SRCR domains. It plays a crucial role in several inflammatory and infectious diseases, including
inhibiting T-cell signaling. In various biological contexts, sepsis and COVID-19, making it a valuable biomarker.
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membrane-bound CD5 undergoes cleavage, resulting Similar to its membrane-bound form, sCD163 aids in the
in the release of soluble CD5 (sCD5). The ectodomain clearance of unbound hemoglobin, reducing oxidative
of CD5 specifically interacts with several fungal species damage. CD163 has emerged as a highly promising
by recognizing β-glucans, key components of fungal therapeutic target due to its selective expression on
23
cell walls. In mouse models of fungal septic shock, macrophages. As such, drug delivery systems such as
administration of recombinant sCD5 led to significant liposomes and antibody-drug conjugates targeting CD163
reductions in pro-inflammatory cytokines such as IL-6 and were used in models of LPS-induced inflammation and
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IL-1β, indicating its therapeutic potential in mitigating cancer, where targeting tumor-associated macrophages
inflammation and enhancing survival during infections. 23 inhibits tumor growth. 37
Similarly, CD6 is primarily expressed in T cells and CD163L1 is prominently expressed and colocalizes
some B cells, and also functions as an inhibitory receptor. with CD163 in various macrophage subsets; however,
24
The ectodomain of CD6 can identify PAMPs, including its expression is low or absent in alveolar macrophages,
lipoteichoic acid derived from Gram-positive bacteria and monocytes, glia, and Kupffer cells. Unlike other
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LPS from Gram-negative bacteria, and also recognize scavenger receptors, CD163L1 has not been demonstrated
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saprophytic, non-pathogenic fungal species. Cell- to function as a PRR, as it does not interact with any
surface CD6 expression can be downregulated through clinically isolated bacterial strains, indicating a distinct
proteolytic cleavage, which contributes to the homeostatic mechanism of action. Its expression is upregulated by anti-
control of ongoing immune responses by increasing inflammatory inducers such as IL-10 and macrophage
T-cell susceptibility to apoptosis and reducing their colony-stimulating factor while being suppressed by pro-
responsiveness to proliferative stimuli. 26 inflammatory mediators such as LPS, TNF-α, and IFN-γ.
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Elevated circulating levels of soluble CD6 (sCD6) and The inflammation-resolving effects of CD163L1 are likely
sCD5 are observed in patients with primary Sjögren’s attributable to its regulatory function in macrophages
syndrome. Recently, an increase in CD6 plasma levels has and its response to specific cytokines rather than direct
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been found to be associated with microbiota modulation interactions with pathogens.
of inflammation in psoriatic arthritis. Indeed, CD6 has
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been investigated as a potential therapeutic target, with 4. Conclusion
itolizumab, a humanized anti-CD6 monoclonal antibody, SRCR proteins, particularly the soluble members such as
being explored for the treatment of inflammatory diseases CD5L, DMBT1, SSC4D, and SSC5D, play vital roles in
such as psoriasis, rheumatoid arthritis, and complications microbial recognition and the regulation of inflammatory
related to COVID-19. 29-31 responses. Their functions as PRRs not only enhance the

Volume 2 Issue 2 (2025) 49 doi: 10.36922/mi.5741