Platelet-derived β2M regulates monocyte inflammatory responses

Hilt, Zachary T.; Pariser, Daphne N.; Ture, Sara; Mohan, Amy; Quijada, Pearl; Asante, Akua A.; Cameron, Scott J.; Sterling, Julie A.; Merkel, Alyssa R.; Johanson, Andrew; Jenkins, Jermaine L.; Small, Eric M.; McGrath, Kathleen E.; Palis, James; Elliott, Michael R.; Morrell, Craig N.

doi:10.1172/jci.insight.122943

Cited by 32 publications

(48 citation statements)

References 44 publications

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“…We previously demonstrated that platelets are a major source of circulating plasma β2M. PF4 Cre -β2M Flox/Flox (Plt-β2M -/-) mice specifically lack β2M in platelets and had reduced plasma β2M compared to wild-type (WT) control mice [8]. Plasma β2M increases with age in both mice and humans [6].…”

Section: During the Aging Process Increased Plasma β2m Correlates Wimentioning

confidence: 99%

“…Compared to young mice, there was a significant increase in P-selectin surface expression on old WT and old Plt-β2M -/isolated platelets, both without agonist stimulation and in a dose dependent manner in response to ADP and high thrombin concentrations ( Supplementary Figure 1). β2M and TGFβ can act antagonistic to each other [8,24], thus we measured plasma TGFβ. There was no significant difference in plasma TGFβ between young or old mice in either genotype ( Figure 1C), while there was a insignificant trend in increased plasma TGFβ in Plt-β2M -/mice compared to WT mice ( Figure 1C).…”

Section: During the Aging Process Increased Plasma β2m Correlates Wimentioning

confidence: 99%

“…Because both β2M and TGFβ are circulating factors that can directly polarize monocytes [8,27,28] we characterized circulating monocyte subsets. WT and Plt-β2M -/mice had no difference in the total number of circulating monocytes (Table 1), but there was a significant increase in the percentage of Ly6C Hi monocytes in old WT mice compared to both WT young and Plt-β2M -/old mice ( Figure 1D).…”

Section: During the Aging Process Increased Plasma β2m Correlates Wimentioning

confidence: 99%

“…Platelets express abundant β2M, and β2M is in the activated platelet releasate [7]. Using platelet specific β2M -/mice (Plt-β2M -/-) generated by our lab, we previously reported that platelets are the major source of plasma β2M and that platelet derived AGING β2M has direct pro-inflammatory effects on monocytes, independent of MHC I trafficking functions [8].…”

Section: Introductionmentioning

confidence: 99%

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Platelet-derived β2m regulates age related monocyte/macrophage functions

Hilt

Ture

Mohan

et al. 2019

Aging

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Platelets have central roles in both immune responses and development. Stimulated platelets express leukocyte adhesion molecules and release numerous immune modulatory factors that recruit and activate leukocytes, both at the sites of activation and distantly. Monocytes are innate immune cells with dynamic immune modulatory functions that change during the aging process, a phenomenon termed "inflammaging". We have previously shown that platelets are a major source of plasma beta-2 microglobulin (β2M) and that β2M induced a monocyte pro-inflammatory phenotype. Plasma β2M increases with age and is a pro-aging factor. We hypothesized that platelet derived β2M regulates monocyte phenotypes in the context of aging. Using wild-type (WT) and platelet specific β2M knockout mice (Plt-β2M-/-) mice, we found that plasma β2M increased with age and correlated with increased circulating Ly6C Hi monocytes. However, aged Plt-β2M-/mice had significantly fewer Ly6C Hi monocytes compared to WT mice. Quantitative real-time PCR of circulating monocytes showed that WT mouse monocytes were more "pro-inflammatory" with age, while Plt-β2M-/derived monocytes adopted a "pro-reparative" phenotype. Older Plt-β2M-/mice had a significant decline in heart function compared to age matched WT mice, as well as increased cardiac fibrosis and pro-fibrotic markers. These data suggest that platelet-derived β2M regulates age associated monocyte polarization, and a loss of platelet derived β2M shifted monocytes and macrophages to a pro-reparative phenotype and increased pro-fibrotic cardiac responses. Platelet regulation of monocyte phenotypes via β2M may maintain a balance between inflammatory and reparative signals that affects age related physiologic outcomes.

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Section: During the Aging Process Increased Plasma β2m Correlates Wimentioning

confidence: 99%

Section: During the Aging Process Increased Plasma β2m Correlates Wimentioning

confidence: 99%

Section: During the Aging Process Increased Plasma β2m Correlates Wimentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

See 2 more Smart Citations

Platelet-derived β2m regulates age related monocyte/macrophage functions

Hilt

Ture

Mohan

et al. 2019

Aging

Self Cite

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“…Specific signals were normalized to GAPDH and the average signal intensity was determined for each proteasomal subunit. Relative expression of the different donors is displayed for each protein related to the mean (donors are representative for >20 donors) [69][70][71][72][73] Activated platelets form aggregates with T cells, which most likely establish immunological synapses between these two cell types. 74 Although platelets mainly express denatured MHC class I heavy chains on their surface, which are adsorbed from plasma and cannot stimulate cytotoxic T lymphocytes (CTL)-mediated cytotoxicity, 75 especially young platelets express intact MHC class I.…”

Section: Pl Atele Ts and Their Rele Van Ce A S Immune And Immunomodmentioning

confidence: 99%

Structure and function of the ubiquitin‐proteasome system in platelets

Colberg

Cammann

Greinacher

et al. 2020

Journal of Thrombosis and Haemostasis

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Platelets are small anucleate blood cells with a life span of 7 to 10 days. They are main regulators of hemostasis. Balanced platelet activity is crucial to prevent bleeding or occlusive thrombus formation. Growing evidence supports that platelets also participate in immune reactions, and interaction between platelets and leukocytes contributes to both thrombosis and inflammation. The ubiquitin‐proteasome system (UPS) plays a key role in maintaining cellular protein homeostasis by its ability to degrade non‐functional self‐, foreign, or short‐lived regulatory proteins. Platelets express standard and immunoproteasomes. Inhibition of the proteasome impairs platelet production and platelet function. Platelets also express major histocompatibility complex (MHC) class I molecules. Peptide fragments released by proteasomes can bind to MHC class I, which makes it also likely that platelets can activate epitope specific cytotoxic T lymphocytes (CTLs). In this review, we focus on current knowledge on the significance of the proteasome for the functions of platelets as critical regulators of hemostasis as well as modulators of the immune response.

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MHC Class I on murine hematopoietic APC selects Type A IEL precursors in the thymus

et al. 2021

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TCRαβ + CD8α + CD8βintestinal intraepithelial lymphocytes (CD8αα IEL) are gut T cells that maintain barrier surface homeostasis. Most CD8αα IEL are derived from thymic precursors (IELp) through a mechanism referred to as clonal diversion. In this model, self-reactive thymocytes undergo deletion in the presence of CD28 costimulation, but in its absence undergo diversion to the IEL fate. While previous reports showed that IELp were largely β2m dependent, the APC that drive the development of these cells are poorly defined. We found that both CD80 and CD86 restrain IELp development, and conventional DCs play a prominent role. We sought to define a CD80/86 negative, MHCI positive APC that supports the development to the IEL lineage. Chimera studies showed that MHCI needs to be expressed on hematopoietic APC for selection. As thymic hematopoietic APC are heterogeneous in their expression of MHCI and costimulatory molecules, we identified four thymic APC types that were CD80/86 neg/low and MHCI + . However, selective depletion of β2m in individual APC suggested functional redundancy. Thus, while hematopoietic APC play a critical role in clonal diversion, no single APC subset is specialized to promote the CD8αα IEL fate.

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Platelet-derived β2M regulates monocyte inflammatory responses

Cited by 32 publications

References 44 publications

Platelet-derived β2m regulates age related monocyte/macrophage functions

Platelet-derived β2m regulates age related monocyte/macrophage functions

Structure and function of the ubiquitin‐proteasome system in platelets

MHC Class I on murine hematopoietic APC selects Type A IEL precursors in the thymus

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