From: The innate immune response to ischemic injury: a multiscale modeling perspective
Rule | Literature support | Relevant references | |
---|---|---|---|
CCL2 and ROS < − from intracellular model | |||
1 | Injury (2)* = 0 if M2 = 1 and previous injury = 1 | M2 macrophages will resolve tissue damage due to injury. | |
2 | DAMPs (3) = 0 if Injury = 0 AND ROS = 0 regardless of M2 | DAMPs are generally not accessible without tissue damage. | |
3 | DAMPs =0 if (Injury = 1 XOR** ROS = 1) and M2 = 1 | M2 macrophages can completely resolve damage due to either injury or ROS. | |
4 | DAMPs =1 if (Injury = 1 XOR** ROS = 1) and M2 = 0 unless previous DAMPs = 2 | Lack of M2 macrophages leads to increased tissue damage in response to injury or ROS unless overwhelming damage. | |
5 | DAMPs =1 if (Injury = 1 AND ROS = 1) and M2 = 1 | Extensive damage resulting from both injury and ROS in the presence of M2 is not completely resolved. | |
6 | DAMPs =2 if (Injury = 1 AND ROS = 1) and M2 = 0 | Excess injury triggers an overwhelming immune response that destroys the tissue in the absence of M2 macrophages. | |
7 | M1 (3) = 0 if (CCL2 = 0) | Pro-inflammatory cytokines (exemplified by CCL2) are required to recruit M1 monocytes/macrophages. | |
8 | M1 = 1 if CCL2 = 1 | Macrophage recruitment is initiated in response to cytokines. | |
9 | M1 = 2 CCL2 = 2 | increased cytokine levels result in more M1 macrophages. | |
10 | M2 (2) = 1 if M1 = 1 | M1 macrophages differentiate into M2. | |
11 | M2 = 0 otherwise | M1s must exist to differentiate into M2s; and overwhelming M1 infiltration overcomes M2. | |
Intracellular scale rules | |||
DAMPs and M2 < − from tissue model | |||
12 | CD13 (2)* = 1 if DAMPs = 1 or 2 | CD13 is phosphorylated upon ligand binding to TLR4 | |
13 | CD13 = 0 otherwise | CD13 is not activated without inflammation | [49] |
14 | TRIF (3) = 0 if DAMPs = 0 regardless of CD13 | There is no response without tissue damage. | |
15 | TRIF = 1 if (DAMPs = 1) and (CD13 = 1) | Ligation and endocytosis of TLR4 triggers TRIF activation. | |
16 | TRIF = 2 if (DAMPs = 1) and (CD13 = 0) | TRIF is hyper-activated in the absence of CD13 | |
17 | TRIF = 2 if DAMPs = 2 regardless of CD13 | Excess injury triggers an overwhelming immune response. | |
18 | IRF3 (3) = TRIF (3) | TRIF activates IRF3 | |
19 | IFN-β (3) = IRF3 | Active IRF3 transcriptionally activates IFN-β | |
18 | ROS (2) = 1 IFNβ = 2 - > to intracellular model | High levels of IFN-β induce ROS | |
19 | ROS = 0 otherwise | Low levels of IFN-β do not induce ROS. | |
20 | MyD88 = DAMPs (3) | DAMPs bind TLR4 and activate MyD88 from the cell surface. | |
21 | pIRAK = MyD88 (3) | Activated MyD88 enables IRAK phosphorylation/activation. | |
22 | NF-kB = 0 if M2 = 1 and (pIRAK = 0 or 1) | M2 macrophages dampen NF-kB activity and halt inflammation unless overwhelming response. | |
23 | NF-kB = pIRAK (3) otherwise | pIRAK activates NF-kB. | |
24 | CCL2 = NF-kB (3) | NF-kB transcriptionally regulates CCL2 |