Neutrophils

Neutrophil Activation and Signal Transduction

Neutrophil Pathophysiology / Functions

Suicidal NETosis leads to chromatin decondensation, nuclear swelling, and membrane perforation
Vital NETosis : nuclear material is lot but neutrophil is not dead and can continue chemotactic and phagocytic abilities

Red: K and F, 10 th edition: Neutrophil-derived microparticles are emancipated cytosol-entrapping vesicles of neutrophil plasma membrane. Like NETs, microparticles are previously unappreciated propagators of neutrophil-mediated outcomes (Figure 11-9). During activation, neutrophils release these heterogeneous vesicles, which range in diameter between 100 and 1000 nm and express surface markers of their parent cells. Microparticles can bind to target cells (including endothelial cells) in a receptor-dependent manner and, in so doing, transfer parent cell messenger RNA (mRNA) and microRNA (miRNA) to drive transcellular responses. Microparticle numbers increase in sepsis, as well as vascular disease, and they also appear to play a significant role in infection-mediated thrombosis.^53-56

LT B4
RefL K and F
The cyclo-oxygenase (COX) (endoperoxide synthase) pathway is the other major pathway of AA metabolism. AA metabolized by COX is converted into prostaglandin H, which undergoes further cell type-specific conversion to a variety of other prostaglandins.⁵⁹ The prostaglandin of most relevance to inflammation is prostaglandin (PG)E₂, whose numerous pro-inflammatory effects include increased vasodilation, vascular permeability, and pain. Interestingly, the direct effects of PGE₂on neutrophils are largely inhibitory, probably through elevations of intra-cellular cAMP.⁶⁰

Ref: K and F, 10th edition
IL-8, IL-12, MIP-1α and β (CCL3 and CCL4), growth-related oncogene-α (GRO-α), oncostatin M, monocyte chemotactic protein (MCP)-1, and TGF. Eg. LPS stimulates TNF production that in turn causes the production of the above mediators
Multiple lines of investigation suggest that neutrophils may also be a source for IL-17, a potent cytokine that can amplify neutrophil migration and recruitment.⁶¹
Of note: Neutrophils do not produce IL-1β, TNF, or IL-6, the classical products of macrophages and synovial cells.⁶²
Activated Neutrophils also release:

BLyS - stimulates B cell proliferation through BAFF-R, TACI, BCMA
TRAIL(TNF associated Apoptosis Inducing Ligands) - induces anti-tumor affect and apoptosis.

Ref: K and F, 10th edition; Neutrophils that accumulate at sites of inflammation do so in concert with aggregating platelets and further enhance platelet aggregation (Figure 11-10). Platelet-neutrophil complexes are elevated in patients with systemic lupus erythematosus and rheumatoid arthritis (RA), likely as a result of neutrophil activation.⁶⁸ On the other hand, in the setting of vascular injury and endothelial damage, platelets activated in response to exposed collagen express P-selectin, promoting neutrophil-platelet associations via neutrophil PSGL-1 counter-receptors. Subsequent activationof neutrophils leads to firmer bonds as a result of integrin CD11b/CD18 adhesion molecule activation.⁶⁹Neutrophil-platelet interactions result in surface expression of tissue factor that can initiate the coagulation cascade.⁷⁰Neutrophil NETs can also play roles in promoting clotting, including disseminated intravascular coagulation.

Hereditary Disorders related to Neutrophil

Neutrophils in Rheumatologic Diseases

Urate crystals are phagocytosed by synovial macrophage - leads to the production of IL1 and IL 8
Neutrophil recruitment is via complement activation by Intraarticular synovial crystals that non-specifically binds Igb and activates classical and alternative pathways . C5a attracts Neutrophils. Neutrophils now phygocytos the Igb bound crystals and in turn release LT B4 , IL 8 and other mediators
Naked Urate crystals can also directly activate neutrophils
NETs plays a role in resolution of inflammation and not in the activation

Ref: K and F, 10th edition
Immune complex deposition is implicit as vasculitis is a secondary phenomenon
Increased adhesion molecules leads to neutrophil ingress in vascular structure
NETs express several autoantigens that are targets of lupus autoantibodies.¹¹³
^{NETs can be dismantled by DNase, and some patients with lupus cannot degrade NETs because of inhibitors of or antibodies to DNase. The inability to degrade NETs correlates with the presence of lupus nephritis.¹¹⁵ Moreover, it was reported that patients with low NET-degrading activity in their sera have higher levels of autoantibodies and lower levels of C3 and C4 compared with patients who have high NET-degrading activity in their sera, because NETs that are not degraded bind and activate complement.¹¹⁶ NETs may also contribute to the IFN-α signature in systemic lupus erythematosus (SLE) because they induce IFN-α production by plasmacytoid dendritic cells in a TLR9-dependent manner.¹¹⁷}

Immune complex deposition in the blood vessel leads to complement activation and influx of neutrophils (immune complex formation is a hall mark of many small vessle vasculitis including HSP, Mixed Cryoglobunemia, Hypersensitivity ). In these disorder, clasis of neutrophil is seen, hence, Leucocytoclastic
Immunex complex independent : Induction of adhesion molecules on endothelial cells, neutrophils themselves, or both is an alternative mechanism through which neutrophil accumulation in vessels may be propagated. Adhesion molecule upregulation may be particularly relevant to vasculitides in which immune complex formation is not a hallmark. It is likely that many rheumatic diseases employ both immune complex–dependent and immune complex–independent mechanisms in the pathogenesis of neutrophil ingress into vascular structures. Belmont and colleagues have shown the induction of adhesion molecules in patients with SLE.¹¹⁹

ANCA associated vasculitis: In these diseases, partial neutrophil degranulation, resulting in exposure of ANCA antigens (e.g., MPO and proteinase 3), appears to be critical for disease pathogenesis.

Neutrophils in Rheumatology - additional topics

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