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Table 2 Tissue Scale Rules

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. [1, 82,83,84]
2 DAMPs (3) = 0 if Injury = 0 AND ROS = 0 regardless of M2 DAMPs are generally not accessible without tissue damage. [85, 86]
3 DAMPs =0 if (Injury = 1 XOR** ROS = 1) and M2 = 1 M2 macrophages can completely resolve damage due to either injury or ROS. [85,86,87,88,89,90,91,92]
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. [85,86,87,88,89,90,91,92]
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. [85,86,87,88,89,90,91,92]
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. [85,86,87,88,89,90,91,92]
7 M1 (3) = 0 if (CCL2 = 0) Pro-inflammatory cytokines (exemplified by CCL2) are required to recruit M1 monocytes/macrophages. [1, 5, 67, 82,83,84, 93]
8 M1 = 1 if CCL2 = 1 Macrophage recruitment is initiated in response to cytokines. [1, 5, 67, 82,83,84, 93]
9 M1 = 2 CCL2 = 2 increased cytokine levels result in more M1 macrophages. [1, 5, 67, 82,83,84, 93]
10 M2 (2) = 1 if M1 = 1 M1 macrophages differentiate into M2. [1, 5, 67, 82,83,84, 93]
11 M2 = 0 otherwise M1s must exist to differentiate into M2s; and overwhelming M1 infiltration overcomes M2. [1, 5, 67, 82,83,84, 93]
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 [49, 71, 94]
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. [25, 49, 95]
15 TRIF = 1 if (DAMPs = 1) and (CD13 = 1) Ligation and endocytosis of TLR4 triggers TRIF activation. [25, 49, 95]
16 TRIF = 2 if (DAMPs = 1) and (CD13 = 0) TRIF is hyper-activated in the absence of CD13 [25, 49, 95]
17 TRIF = 2 if DAMPs = 2 regardless of CD13 Excess injury triggers an overwhelming immune response. [25, 49, 95]
18 IRF3 (3) = TRIF (3) TRIF activates IRF3 [25, 49, 95]
19 IFN-β (3) = IRF3 Active IRF3 transcriptionally activates IFN-β [19, 49, 73, 96, 97]
18 ROS (2) = 1 IFNβ = 2 - > to intracellular model High levels of IFN-β induce ROS [49, 87, 88, 90,91,92]
19 ROS = 0 otherwise Low levels of IFN-β do not induce ROS. [49, 87, 88, 90,91,92]
20 MyD88 = DAMPs (3) DAMPs bind TLR4 and activate MyD88 from the cell surface. [98,99,100]
21 pIRAK = MyD88 (3) Activated MyD88 enables IRAK phosphorylation/activation. [98,99,100]
22 NF-kB = 0 if M2 = 1 and (pIRAK = 0 or 1) M2 macrophages dampen NF-kB activity and halt inflammation unless overwhelming response. [98,99,100]
23 NF-kB = pIRAK (3) otherwise pIRAK activates NF-kB. [67, 93]
24 CCL2 = NF-kB (3) NF-kB transcriptionally regulates CCL2 [98,99,100]
  1. *# of states for the node; **XOR - either or
  2. CCL2 and ROS - > to tissue scale